Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

Abstract

The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes.

Genetic–epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity

“…Our reporter assays showed a more efficient effect of PLZF when both binding sites were intact and the diseaseassociated allele was present at rs12101261. These results are consistent with previous data by us and others demonstrating the importance of disease-associated SNPs in noncoding regions in impacting transcriptional mechanisms by interrupting TF binding sites (6,29) or by disturbing long-range interactions (30). (B) Correlation between TSHR and PLZF mRNA levels in thymus tissues from individuals who were homozygous TT (n = 9), homozygous CC (n = 11), and heterozygous CT (n = 19) for the rs12101261 SNP.…”

Functional evaluation of the role of C-type lectin domain family 16A at the chromosome 16p13 locus

“…Aside from the tight LD observed in the associated locus, the pursuit of revealing the diseasecausing variant has been hindered by the lack of association of nsSNPs [1,8,12] and inconclusive evidence that the associated intronic SNPs exert transcriptional effects on CLEC16A and its surrounding genes [1,[13][14][15] and Marchand et al 2009 and Zouk et al 2102 (unpublished results). Therefore, before uncovering such potential causal variants, it is imperative that we gain more insight into the largely unknown function of the CLEC16A protein to decipher how these variants, when discovered, would affect protein function and consequent disease pathology.…”

Contribution of Rare and Common Genetic Variants to Plasma Lipid Levels and Carotid Stiffness and Geometry

“…This intronic region, where several of the disease-associated variants are located, is highly enriched in transcription binding sites. 32 In the same report, it was shown that alleles of CLEC16A that confer protection from type 1 diabetes mellitus and multiple sclerosis were associated with increased expression of DEXI in 2 human monocyte data sets, leading to the conclusion that DEXI may be an unappreciated autoimmune candidate gene. In addition to DEXI, 2 nearby genes SOCS1 and CIITA are other possible immunity and inflammation-related candidates.…”